Monitoring brain neural activity

ABSTRACT

Monitoring brain neural activity comprises repeatedly applying electrical stimuli to evoke neural responses in the brain. Neural responses evoked by the stimuli are recorded. The recorded neural responses are assessed for changed characteristics over time, to monitor a time-varying effect on the recorded neural responses of local field potentials arising from a source other than the electrical stimuli.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application in s national stage of Application No.PCT/AU2016/050431, filed May 31, 2016, which application claims thebenefit of Australian Provisional Patent Application No. 2015902022,filed May 31, 2015, the disclosures of which are incorporated herein byreference in their entireties.

TECHNICAL FIELD

The present invention relates to neural modulation in the brain, and inparticular relates to a method for monitoring neural responses in thebrain evoked by electrical stimulation, and monitoring such recordingsrepeatedly over time, in order to detect and monitor local fieldpotentials arising from other sources.

BACKGROUND OF THE INVENTION

Neuromodulation involves applying an electric stimulus to biologicaltissue in order to evoke compound action potentials (ECAPs) to produce atherapeutic effect. Neuromodulation can be non-invasive such as bytranscutaneous electrical nerve stimulation (TENS), transcranialmagnetic stimulation (TMS), or highly invasive when requiring theimplantation of one or more electrodes and a controlling stimulator asin the case of deep brain stimulation (DBS). DBS has become the mosteffective treatment for late stage Parkinson's disease, but is a highlyinvasive therapy requiring the implantations of one or more leads deepinto subcortical nuclei and connection to one or more pulse generatorsimplanted in the chest. Many DBS electrode target structures have beenstudied to treat a wide variety of diseases, and the preferred locationof the electrode varies depending on the disease that is being treated.In the case of Parkinson's disease, the preferred targets are theinternal segment of the globus pallidus (GPi) and the subthalamicnucleus (STN). The GPi has also been targeted for Huntington's diseaseand Tourette's syndrome, the nucleus accumbens has been targeted forchronic depression and alcohol dependence, and the fornix, hypothalamusand nucleus basalis of Meynert have been targeted for Alzheimer'sdisease.

Parkinson's disease is a degenerative disorder affectingdopamine-releasing cells in the substantia nigra. Many theoriesdescribing the functioning of the basal ganglia and how thisdegeneration relates to Parkinson's disease have been proposed, howeverall such theories have significant inadequacies in describing allaspects of Parkinson's disease, and understanding the mechanisms of DBSremains the focus of considerable research effort.

Any discussion of documents, acts, materials, devices, articles or thelike which has been included in the present specification is solely forthe purpose of providing a context for the present invention. It is notto be taken as an admission that any or all of these matters form partof the prior art base or were common general knowledge in the fieldrelevant to the present invention as it existed before the priority dateof each claim of this application.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

In this specification, a statement that an element may be “at least oneof” a list of options is to be understood that the element may be anyone of the listed options, or may be any combination of two or more ofthe listed options.

SUMMARY OF THE INVENTION

According to a first aspect the present invention provides a method ofmonitoring brain neural activity, the method comprising:

repeatedly applying electrical stimuli to evoke neural responses in thebrain;

recording neural responses evoked by the stimuli,

assessing the recorded neural responses for changed characteristics overtime, to monitor a time-varying effect on the neural responses of localfield potentials arising from a source other than the electricalstimuli.

According to a second aspect the present invention provides a brainneurostimulator device comprising:

at least one stimulus electrode configured to be positioned in the brainand to deliver electrical stimuli to the brain;

at least one sense electrode configured to be positioned in the brainand to sense neural responses evoked by the stimuli;

a pulse generator configured to apply electrical stimuli from the atleast one stimulus electrode to the brain;

measurement circuitry configured to record brain neural responses sensedby the at least one sense electrode in response to the electricalstimuli; and

a processor for assessing the recorded neural responses for changedcharacteristics over time, to monitor a time-varying effect on theneural responses of local field potentials arising from a source otherthan the electrical stimuli.

The present invention further provides computer software, or a computerprogram product comprising computer program code means, or anon-transitory computer readable medium, or a computing device operatingunder the control of said software or product, configured to repeatedlyapply electrical stimuli to evoke neural responses in the brain, andfurther configured to record neural responses evoked by the stimuli, andfurther configured to assess the recorded neural responses for changedcharacteristics over time, to monitor a time-varying effect on theneural responses of local field potentials arising from a source otherthan the electrical stimuli.

The neurostimulator may comprise a deep brain stimulator.

Assessing the recorded neural responses for changed characteristics maycomprise assessing the amplitude of the observed neural responses. Theobserved neural responses may be assessed in the frequency domain.Amplitude variations arising in the 0.6 to 3 Hz range may enable aheartbeat of the subject to be assessed. Such embodiments recognise thatthe heartbeat affects the local field potential at the recordingelectrodes mechanically or rheologically, introducing a modulation orfluctuation onto the observed ECAP amplitude.

Fluctuations in the amplitude of the observed evoked ECAPs in the 7-35Hz range, also referred to as beta-band oscillations, may be indicativeof a Parkinson's patient's OFF state, or in the 50-1000 Hz range may beindicative of a Parkinson's patient's ON state. Spectral analysis mayenable some embodiments to simultaneously assess each such signal ofneural activity from sources other than the neurostimulator.

It is thus to be understood that the local field potentials arising froma source other than the electrical stimuli is intended to encompasslocal field potential variations arising mechanically, rheologically,neurologically or the like. In the case of beta band oscillations inparticular it is to be noted that the stimuli applied by theneurostimulator may effect a therapy which alters such beta bandoscillations, even though such mechanisms are poorly understood. Thereis thus a distinction to be noted between a locally evoked neuralresponse or ECAP which arises directly from a stimulus, and the separatecontribution of a beta band oscillation which modulates the amplitude orspectral content of a series of such ECAPs over time. The separatecontribution of beta band oscillations is to be understood asconstituting a source other than the electrical stimuli and thus withinthe scope of some embodiments of the present invention.

The neural measurement is preferably obtained in accordance with theteaching of International Patent Publication No. WO2012/155183 by thepresent applicant, the content of which is incorporated herein byreference.

By monitoring a time-varying effect of local field potentials arisingfrom a source or sources other than the electrical stimuli, someembodiments of the present invention may deliver a diagnostic method.The presence, amplitude, morphology, and/or latency of the neuralresponse effects arising from the other source(s) may be compared tohealthy ranges and/or monitored for changes over time in order todiagnose a disease state. The method of the invention may be applied insome embodiments in order to determine a therapeutic effect of thestimulation, determine a therapeutic effect of medicine, and/or tomonitor disease state. A therapeutic response may subsequently beordered, requested and/or administered based on the diagnosis.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the invention will now be described with reference to theaccompanying drawings, in which:

FIG. 1 illustrates an implanted deep brain stimulator;

FIG. 2 is a block diagram of the implanted neurostimulator;

FIG. 3 is a schematic illustrating interaction of the implantedstimulator with brain tissue;

FIG. 4 illustrates the dynamics of evoked response amplitude in onepatient on two separate recording channels, in the time domain,

FIG. 5 illustrates the frequency domain analysis of the dynamics of theECAP amplitude;

FIG. 6 illustrates the spectrum of observed ECAPs in the STN; and

FIG. 7a shows an ECG spectrum, and FIG. 7b shows the spectrum of ECAPs,illustrating the presence of heartbeat in the ECAPs spectrum.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 schematically illustrates an implanted deep brain stimulator 100.Stimulator 100 comprises an electronics module 110 implanted at asuitable location in the patient's chest, and two electrode assemblies150, 152 implanted within the brain and connected to the module 110 by asuitable lead. Numerous aspects of operation of implanted neural device100 are reconfigurable by an external control device (not shown).Moreover, implanted neural device 100 serves a data gathering role, withgathered data being communicated to an external device.

FIG. 2 is a block diagram of the implanted neurostimulator 100. Module110 contains a battery 112 and a telemetry module 114. In embodiments ofthe present invention, any suitable type of transcutaneous communication190, such as infrared (IR), electromagnetic, capacitive and inductivetransfer, may be used by telemetry module 114 to transfer power and/ordata between an external device and the electronics module 110.

Module controller 116 has an associated memory 118 storing patientsettings 120, control programs 122 and the like. Controller 116 controlsa pulse generator 124 to generate stimuli in the form of current pulsesin accordance with the patient settings 120 and control programs 122.Electrode selection module 126 switches the generated pulses to theappropriate electrode(s) of electrode arrays 150 and 152, for deliveryof the current pulse to the tissue surrounding the selectedelectrode(s). Measurement circuitry 128 is configured to capturemeasurements of neural responses sensed at sense electrode(s) of theelectrode arrays as selected by electrode selection module 126.

FIG. 3 is a schematic illustrating interaction of the electrode array150 of implanted stimulator 100 with nerve tissue 180, in this case thesubthalamic nucleus however alternative embodiments may be positionedadjacent any suitable brain structure. Array 152 is not shown in FIG. 3but operates in an equivalent manner in the contralateral cerebralhemisphere. Electrode selection module 126 selects a stimulationelectrode 2 of electrode array 150 to deliver an electrical currentpulse to surrounding neural tissue 180, and also selects a returnelectrode 4 of the array 150 for stimulus current recovery to maintain azero net charge transfer.

Delivery of an appropriate stimulus to the neural tissue 180 evokes aneural response comprising a compound action potential which willpropagate along associated neural pathways, for therapeutic purposes.

The device 100 is further configured to sense the existence andintensity of compound action potentials (CAPs) propagating within neuraltissue 180, whether such CAPs are evoked by the stimulus from electrodes2 and 4, or otherwise evoked such as by the contralateral electrodes ofarray 152. To this end, any electrodes of the array 150 may be selectedby the electrode selection module 126 to serve as measurement electrode6 and measurement reference electrode 8. Signals sensed by themeasurement electrodes 6 and 8 are passed to measurement circuitry 128,which for example may operate in accordance with the teachings ofInternational Patent Application Publication No. WO2012155183 by thepresent applicant, the content of which is incorporated herein byreference.

The present invention recognises that the recorded neural responsesmeasured as a function of the stimulus can provide a great deal ofinformation about the neurons that are being stimulated and theircharacteristics. This information can play a vital role not only inchoosing parameters for stimulation but also in monitoring the course ofthe disease. The shape of the compound action potential is directlyrelated to the electrophysiology and the ion channel conductivitiesduring the time course of the evolution of the action potential. Theshape is reflective of the underlying ion channel behaviour which is inturn reflective of the underlying disease state.

The present invention recognises that a plethora of causes can changethe response of the tissue to stimulation, including adaptation, changesin electrode micro environment co-incident with the heartbeat, aworsening of the state of the disease, the course of medication intake,the current overall state of the patient (sleep, rest, movement, etc.).Further, it is possible to use ECAPs to analyse dynamics of such othersources of neural activity.

Parkinson's disease has often been associated to an increase inbeta-band oscillations which can be influenced by deep brainstimulation. We have shown that measurements of evoked compound actionpotentials (ECAPs) can be used to analyse the frequency spectrum of thesignals in the brain by observing the modulation of the ECAP amplitude.

The modulation observed directly reflects slow oscillations in the brainand a feedback system can be designed that stimulates and records theslow waves in real-time by means of the ECAP amplitude. The feedback canbe adjusted to optimise the stimulation parameters in order to minimiseor maximise certain frequency bands (for example the beta-band forParkinson's disease).

The frequency analysis of the ECAP features can also be used to extractother physiological information from the patient like the heartbeat thatcan help provide a more complete picture of the patient's state duringthe course of the disease. FIGS. 4 and 5 give an example of the dynamicchanges that can be observed with the embodiment of the presentinvention.

FIG. 4 illustrates the dynamics of the |N1-P2| amplitude in one patienton two separate recording channels in the time domain. FIG. 5 shows thefrequency analysis of the dynamics of the |N1-P2| amplitude on one ofthe patients.

Heartbeat induced fluctuations in the ECAP amplitude may for example becontrolled by feedback, in order that the evoked response amplituderemains constant, or remains upon a desired locus, throughout eachcardiac cycle. Additionally or alternatively, medication inducedfluctuations in neural excitability and thus the ECAP amplitude may becontrolled by feedback, in order for the evoked response amplitude toremain constant, or remain upon a desired locus, throughout the courseof each dose of a medication such as L-dopa for Parkinson's disease.

Thus, the ECAP amplitude is modulated by slow potentials, making ECAPamplitude measurements a proxy measure for at least some of the observedfrequency components. In the STN, the focus is guided toward beta-bandoscillations, in the VIM, the tremor frequencies are considered.

FIG. 6 is a plot of the frequency components of the first 1000consecutive stimuli (total measurement time of 7.7 seconds) for 4different stimulation current amplitudes, in the right STN of Patient 1,as measured on electrode R4 with bipolar biphasic stimulation onelectrodes R1/R2. Sharp low frequency peaks in the beta range of thetype seen in FIG. 6 were observed in nearly every one of the five STNpatients assessed, but the location of each peak varied from patient topatient and no net increase or decrease could be observed withincreasing stimulus amplitude. For example, in Patient 1 in FIG. 6, apeak at 1.156 Hz was observed. The next peak appeared at roughly 7 Hzand was followed by periodic peaks at 7 Hz intervals with another peakat around 18 Hz. The peaks change across nuclei. The periodicity of thepeaks suggests that most of the higher frequency peaks are harmonics ofthe same fundamental. This would suggest that in this patient,oscillatory behaviour at around 1 Hz, 7 Hz and 18 Hz is present in thesignal.

The local field potentials (LFPs) sensed by the recording electrodes arethe sum of all electrical activity in the tissue surrounding theelectrodes. This activity thus has a modulatory effect on the observedECAP amplitude. Phase amplitude coupling and pulsed inhibition are twoknown aspects of modulation of nerve excitability with LFPs. The lowestpeak in the frequency spectrum was linked to heartbeat by simultaneousECG and ECAP measurements in Patient 3, as shown in FIGS. 7a and 7b . Inparticular, the ECG spectrum of FIG. 7a shows a heartbeat contributionat 1.557 Hz (approx. 93 beats per minute), corresponding closely to andthus confirming the source of the peak at 1.56 Hz seen in the ECAPspectrum of FIG. 7b . In more detail, FIG. 7b shows the frequencyspectrum of the ECAP amplitude on electrode R4 (right) at 2.5 mAstimulation with a pulse width of 90 μs and a frequency of 130 Hz inPatient 3. It is noted that Patient 3 was assessed in a Sao Paulo trialwhich suffered large measurement artefact leading to the apparentexponential spectral profile, but the peak at 1.56 Hz neverthelessemerges above the significant artefact in FIG. 7b , supporting theobservation of heartbeat from the ECAP spectrum.

The origins of the other peaks at 7 Hz and 18 Hz in FIG. 6 are presentlyunknown, but even so they nevertheless present biomarkers which can betracked over time and by which disease progression or other biologicalchanges may be assessed. Oscillations in the beta range (8-35 Hz), asmeasured through LFPs, have been proposed as a biomarker for Parkinson'sdisease, and disruption of such oscillations has been proposed as amarker of the therapeutic effectiveness of DBS. Beta-band oscillationsseem to play a role in PD and symptomatic relief through DBS therapy,but they cannot explain why levodopa (the most widely usedanti-parkinsonian medication) and DBS, although having similar clinicaleffects, do not affect the beta-band oscillations in a similar way.Embodiments of the present invention provide a means whereby the effectof a given therapy on such oscillations may be effectively observed.

Thus it has been shown that the ECAP amplitude is modulated by at leastsome of the slow oscillations, including heartbeat, and can be used as aproxy to measure these frequency components. Some embodiments of theinvention may therefore implement frequency analysis capability in theimplant, where storage and processing is limited. By storing the ECAPamplitude at each shot, slow oscillations of frequencies of up to halfthe stimulus frequency (the Nyquist frequency) can be retrieved so longas they modulate the local field potential and thus the observed ECAP.

Some embodiments of the invention may thus provide a means whereby animplantable neurostimulator may detect neural activity arising fromsecondary sources, without the need to provide any additional sensorssuch as EEG, EMG or ECoG sensors or the like, and without even the needto interrupt therapeutic electrical stimulation. Such observations mayin turn be used to determine a therapeutic effect of the stimulation,determine a therapeutic effect of medicine, and/or to monitor a diseasestate. A therapeutic response may subsequently be indicated, ordered,requested and/or administered based on the diagnosis.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notlimiting or restrictive.

The invention claimed is:
 1. A method of monitoring brain neuralactivity, the method comprising: repeatedly applying electrical stimulito evoke evoked compound action potentials in a brain; recording evokedcompound action potentials evoked by the stimuli, assessing the recordedevoked compound action potentials for changed characteristics over time,to monitor a time-varying effect of local field potentials on the evokedcompound action potentials, the local field potentials arising from asource other than the electrical stimuli.
 2. The method of claim 1,wherein assessing the recorded evoked compound action potentialscomprises assessing the amplitude of the recorded evoked compound actionpotentials.
 3. The method of claim 1 wherein assessing the recordedevoked compound action potentials comprises assessing spectral contentof the recorded evoked compound action potentials.
 4. The method ofclaim 3, further comprising assessing amplitude variations arising in arange of 0.6 to 3 Hz so as to assess a heartbeat.
 5. The method of claim3, further comprising assessing amplitude variations arising in abeta-band oscillation range of 7-35 Hz.
 6. The method of claim 1 whereinthe time-varying effect is compared to healthy ranges and/or monitoredfor changes over time in order to diagnose a disease state.
 7. Themethod of claim 1 wherein the to time-varying effect is compared tohealthy ranges and/or monitored for changes over time in order todetermine a therapeutic effect of a therapy.
 8. The method of claim 1,further comprising indicating a therapeutic response, based on thetime-varying effect.
 9. A brain neurostimulator device comprising: atleast one stimulus electrode configured to be positioned in a brain andto deliver electrical stimuli to the brain; at least one sense electrodeconfigured to be positioned in the brain and to sense evoked compoundaction potentials evoked by the stimuli; a pulse generator configured toapply electrical stimuli from the at least one stimulus electrode to thebrain; measurement circuitry configured to record brain evoked compoundaction potentials sensed by the at least one sense electrode in responseto the electrical stimuli; and a processor for assessing the recordedevoked compound action potentials for changed characteristics over time,to monitor a time-varying effect of local field potentials on the evokedcompound action potentials, the local field potentials arising from asource other than the electrical stimuli.
 10. A computer program productcomprising computer program code means for monitoring brain neuralactivity, the computer program code means configured to: repeatedlyapply electrical stimuli to evoke evoked compound action potentials inthe brain; record evoked compound action potentials evoked by thestimuli; and assess the recorded evoked compound action potentials forchanged characteristics over time, to monitor a time-varying effect oflocal field potentials on the evoked compound action potentials, the oflocal field potentials arising from a source other than the electricalstimuli.
 11. The brain neurostimulator device of claim 9, wherein theprocessor is further configured to assess the recorded evoked compoundaction potentials by assessing the amplitude of the recorded evokedcompound action potentials.
 12. The brain neurostimulator device ofclaim 9 wherein the processor is further configured to assess therecorded evoked compound action potentials by assessing spectral contentof the recorded evoked compound action potentials.
 13. The brainneurostimulator device of claim 12 wherein the processor is furtherconfigured to assess amplitude variations arising in a range of 0.6 to 3Hz so as to assess a heartbeat.
 14. The brain neurostimulator device ofclaim 12, wherein the processor is further configured to assessamplitude variations arising in a beta-band oscillation range of 7-35Hz.
 15. The brain neurostimulator device of claim 9 wherein theprocessor is further configured to compare the time-varying effect tohealthy ranges, and/or monitor the time-varying effect for changes overtime, in order to diagnose a disease state.
 16. The brainneurostimulator device of claim 9 wherein the processor is furtherconfigured to compare the time-varying effect to healthy ranges, and/ormonitor the time-varying effect for changes over time, in order todetermine a therapeutic effect of a therapy.
 17. The brainneurostimulator device of claim 9 wherein the processor is furtherconfigured to indicate a therapeutic response, based on the time-varyingeffect.